Neuroproteomics Group, University Medical Center, Faculty of Medicine, University of Geneva, Switzerland.
J Proteomics. 2009 Nov 2;73(1):10-29. doi: 10.1016/j.jprot.2009.07.007. Epub 2009 Jul 24.
During the last decades, considerable advances in the understanding of specific mechanisms underlying neurodegeneration in Parkinson's disease have been achieved, yet neither definite etiology nor unifying sequence of molecular events has been formally established. Current unmet needs in Parkinson's disease research include exploring new hypotheses regarding disease susceptibility, occurrence and progression, identifying reliable diagnostic, prognostic and therapeutic biomarkers, and translating basic research into appropriate disease-modifying strategies. The most popular view proposes that Parkinson's disease results from the complex interplay between genetic and environmental factors and mechanisms believed to be at work include oxidative stress, mitochondrial dysfunction, excitotoxicity, iron deposition and inflammation. More recently, a plethora of data has accumulated pinpointing an abnormal processing of the neuronal protein alpha-synuclein as a pivotal mechanism leading to aggregation, inclusions formation and degeneration. This protein-oriented scenario logically opens the door to the application of proteomic strategies to this field of research. We here review the current literature on proteomics applied to Parkinson's disease research, with particular emphasis on pathogenesis of sporadic Parkinson's disease in humans. We propose the view that Parkinson's disease may be an acquired or genetically-determined brain proteinopathy involving an abnormal processing of several, rather than individual neuronal proteins, and discuss some pre-analytical and analytical developments in proteomics that may help in verifying this concept.
在过去的几十年中，人们对帕金森病中神经退行性变的特定机制有了相当大的了解，但尚未确定病因或统一的分子事件序列。目前帕金森病研究中的未满足需求包括探索关于疾病易感性、发生和进展的新假设，确定可靠的诊断、预后和治疗生物标志物，并将基础研究转化为适当的疾病修饰策略。最流行的观点认为，帕金森病是由遗传和环境因素以及被认为起作用的机制之间的复杂相互作用引起的，这些机制包括氧化应激、线粒体功能障碍、兴奋性毒性、铁沉积和炎症。最近，大量数据积累表明，神经元蛋白α-突触核蛋白的异常处理是导致聚集、包涵体形成和变性的关键机制。这种以蛋白质为导向的情况为将蛋白质组学策略应用于该研究领域提供了合理的依据。我们在此回顾了应用于帕金森病研究的蛋白质组学的当前文献，特别强调了人类散发性帕金森病的发病机制。我们提出的观点是，帕金森病可能是一种获得性或遗传性脑蛋白病，涉及几种而不是单个神经元蛋白的异常处理，并讨论了蛋白质组学中一些分析前和分析上的进展，这些进展可能有助于验证这一概念。
